Congestive heart failure is an important medical problem resulting in significant morbidity and mortality. Heart failure occurs at an increased incidence in patients with diabetes mellitus. In addition to an increased propensity for coronary vascular disease, resulting in an ischemic heart disease, a diabetic cardiomyopathy occurs in combination with or independent of coronary vascular disease. In the diabetic heart, abnormal Ca2+ handling during the contractile cycle results in a decreased upstroke phase of the Ca2+ transient due to diminished release of Ca2+ from the sarcoplasmic reticulum (SR) by the ryanodine receptor (RyR2) (22). In addition, the diastolic decline of the Ca2+ transient is diminished due to a reduced activity of the SERCA2a pump (4). Recently developed approaches are aimed at improving the abnormal Ca2+ flux of the heart using viral vector based delivery of proteins to cardiac myocytes, resulting in normalization of the Ca2+ transient and improved contractile function. The identification of novel calcium modulating proteins suitable for viral vector based delivery is therefore of interest to gain additional insight into the components governing calcium homeostasis in the cardiac myocyte and to potentially provide novel strategies for therapeutic intervention to achieve improved contractile function.
One such calcium modulating protein is sorcin, a 21.6 kDa Ca2+ binding protein which is a member of the penta EF-hand family (11). Sorcin)was initially identified in multidrug-resistance cells, where it is overexpressed due to a shared locus encompassing both the multidrug-resistance P-glycoprotein (mdr1) and the sorcin gene (12). Sorcin is expressed in a wide variety of mammalian tissues, including heart and skeletal muscle (13). However, the function of sorcin remains speculative both related to multidrug resistance and to other functions, derived from its effects in excitable cells like neurons (6) and skeletal muscle (14). Sorcin has a wide tissue distribution and highly conserved amino acid sequence among species suggesting that its biological role transcends its potential involvement in multidrug resistance.
Sorcin translocates from the cytosol to membranes upon binding of calcium. Translocation takes place at micromolar calcium concentrations, and it is reversed when the cation concentration is lowered by addition of EGTA (15, 27). Translocation from the cytosol to membranes allows sorcin to interact with specific target proteins. In cardiac cells, sorcin localizes to junctions between the transverse tubule system and junctional sarcoplasmic reticulum and antisera against either sorcin or the cardiac RyA2 precipitate both proteins (13). Furthermore, sorcin decreases the open probability of single RyR2 reconstituted in lipid bilayers (9). Therefore, sorcin may play a role in modulating intracellular Ca2+ levels in the heart (25). More recently, an association of sorcin with the pore-forming subunit of voltage-dependent L-type Ca2+ channels was found (14), however, the functional implication of this association is unknown.